The odontoblasts produce the dentin, which consists in mature tooth or the tooth during tooth development phase. During dentinogenesis, the odontoblasts form dentinal tubules. Dentin cell processes in these tubules make dentin a living tissue. During the primary stage of dentinogenesis, the odontoblasts synthesize, secrete and re-absorb the dentin matrix components. Protein synthesis occurs within cells. Exocytosis and endocytosis occurs mainly in cell processes. The first material formed is unmineralized mantle dentin matrix, mainly including collagen secreted by cells and non-collagenous components. The fasciculata collagen fibers congregate to a ball structure. Due to the continual increase of new fibrils, collagen becomes closer and closer. As a result, these prophase collagen fibers change into collagen fibers. Thus predentin characterized by collagen matrix is formed. Later, the mineralization crystals gradually deposited to become dentin at some distance away from cells.
The mature dentin contains more inorganic minerals than the bone. 65 wt. % of dentin are minerals, mostly hydroxyapatite crystals. Organic materials are 20%, mainly collagenous proteins and non-collagenous proteins. These collagens offer braces to the deposition of hydroxyapatite plate like crystalline.
Type I collagen is predominant (about 97%) in dentin collagens, 10%-15% of which is type I collagen trimer. Different from other connective tissue, type III collagen is lacking in dentin. Moreover, there are types V and VI collagens in dentin, but the contents are small. Although the contents of non-collagenous proteins in dentin are small, there are various kinds. According to the source of proteins, the dentin noncollagenous proteins can be divided to four kinds: dentin specific protein, mineralized tissue specific protein, aspecific protein, and blood serum source protein (or dentin affinity protein). Dentin specific protein is the only one which is synthesized and secreted by odontoblasts and exists only in dentin. Mineralized tissue specific proteins means those that are found and exist not only in dentin but also in cementum and bone. They are synthesized and secreted by osteoblasts, odontoblasts and cementoblasts. The non-specific proteins exist both in dentin and other tissues, including parenchyma, and synthesized and secreted by odontoblasts and other kinds of cells. Blood serum source proteins are those which are synthesized by other cells in the body, mainly by liver cells, and secreted to serum. These proteins have a high affinity to dentin, though they are not synthesized by dentin. They can enter dentin by blood circulation, so they are also called dentin affinity proteins. Proteoglycans or PGS are other primary non-collagenous proteins in dentin. They are large covalent molecules formed by many anylose side chains and one core protein. These side chains are composed of repeating disaccharide chain units, each of which consists of one glycuronic acid and one N-acetamidoacetose. One function of PGS in dentinogenesis is to affect or even control the systematism of collagen skeleton in predentin. The dentin proteoglycans fixed on the solid bracket can induce the formation of hydroxyapatite in vivo and in physiologic pH and ionic condition in vitro. On the contrary, the liquid proteoglycans restrain the form of mineral components in vitro. The combination of PGS and Ca2+ is the precondition of inducing the formation of hydroxyapatite.
Dentinogenesis imperfecta or DGI is an autosomal dominant dental genetic disease that has a prevalence of 1/8000. There are three types according to clinical taxonomy(1) (The number in brackets shows the relative literature.). Dentinogenesis imperfecta Type I is also named DGI-I. Except for dentinogenesis imperfecta, patients usually have osteogenesis imperfecta The pathogeny is broad mutations in collagen type I gene(2). Type II or DGI-II is also called hereditary opalescent dentin. DGI-II has a relationship with the improper mineralization of dentin and its penetrance is nearly 100%(3). Type III or DGI-III is also called dentinogenesis imperfecta Brandywine type or isolate hereditary opalescent dentin. It is a special hereditary opalescent dentin, only found in three isolates in Washington, D.C., the State of Maryland, USA. Witkop first reported this illness in 1956(4) and there is no related report in China till now. DGI-III has an obviously genetic heterogeneity. Its pathogeny is related to malamineralization. Because the gene causing DGI-I has been found and DGI-III is only found in the isolates in the State of Maryland, USA, DGI-II becomes the focus of tooth endodontics.
The clinical symptoms and pathology changes of DGI-II are as follows. The malajustment and turbulence of mineralization result in embryonic layer dysplasia in dentin. Both the primary dentition and permanent dentition are affected, with a more serious damage in primary dentition. A predominant feature is a blue-gray or amber brown discoloration of the teeth. The improper mineralized dentin is soft and the crown is prone to be worn. Moreover, compensatory hyperplasia of matrix increases in improperly mineralized dentin, leading to small or obliterated pulp chambers. Radiographs reveal that the affected teeth have bulbous crowns, narrow roots and small or obliterated pulp chambers and root canals. The pathology shows that the enamel surface is normal, but hypoplasia and hypocalcification can be found in about ⅓ of the patients. The enamel dentin junction changes greatly. Some teeth have a non-obvious sector structure in the enamel dentin junction. However, others are especially obvious. Dentin is lamellar with nearly normal outerdentin and dentinal tubules having subdivisional branches. In other parts, the dentin is obviously abnormal. Some short tubules or tubules with abnormal form distribute in dentin matrix disorderly. The predentin zone is very wide. Along the plywood, the remaining embedded cell can be seen, similar to embedded odontoblast and bloods. Observation under electron microscope indicates that the form and size of hypoplastic dentin micro-crystal are unchanged, but the quantity is small. Uncalcified or partly calcified transverse collagen fasciculi and volumes of crystal space can be seen discontinuously.
For the mapping of DGI-II gene, in 1969, Bixler et al.(5) tried to use some protein polymorphic markers, such as ABO, Rh, MNSs, Kell, Fy, JK, HP, ACP1, PGM1 and PTC, to perform a linkage analysis in DGI-II families, but they failed to get the linkage evidence. In 1977, Mikkelsen et al.(6) mapped a group of specific components (GC) in Vitamin D conjugated protein to 4q11-q13. In the next year, Kühnl identified that GC included six phenotypes: GC2/2, 2/1+, 2/1−, 1+/1−, 1+/1+, and 1−/1−. Later, Ball. S. P. et al.(7) analyzed the linkage in a DGI-II big family named Family MRC4000 with the polymorphic markers of GC and found that DGI-II had a close linkage with GC (Lod=+7.9, θ=0.13). In 1992, Crall et al.(8) mapped DGI-II to interval defined by two protein polymorphic markers: GC and interferon-inducible cytokine INP-10. The relative chromosome location was 4q12-21. The results above only offered a gross orientation of disease gene of DGI-II. Under that condition, it was almost impossible to clone the disease gene in this region.
In 1995, Crosby A.H et al(9) analyzed the linkage in two big DGI-II families with 9 short tandem repeat polymorphic markers (STRP) and mapped the disease gene to the 4q21-23 region defined by two STRPs of D4S2691 and D4S2692. Multipoints linkage analysis suggested that the disease gene might be in the region within about 3.2 cM around SPP1. Recently, Aplin H. M et al.(10) genotyped two big families used by Crosby A. H with 5 hyperdense STRPs. The linkage analysis showed that the disease gene of DGIII located between two STRPs of GATA62A11 and D4S1563 with a genetic distance of 2 cM. Moreover, this research group established the YACs Contigs in this region. They also identified that DMP1, IBSP, SPP1 and DSPP are all in this candidate region by PCR technology.
However, the mechanism of dentinogenesis imperfecta type II is still unclear so far. Also the direct relationship between dentinogenesis imperfecta type II and some special kind of protein is not reported.
In addition, there is still no effective method to diagnose DGI-II early and/or antenatally and to cure DGI-II by non-operative treatment in the art.
Therefore, there is an urgent need to develop new and efficient methods to diagnose and cure DGI-II, the relative pharmaceuticals, and diagnostic technology and reagents.